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Rare Genetic Variants in Complement Factor I Lead to Low FI Plasma Levels Resulting in Increased Risk of Age-Related Macular Degeneration

Lookup NU author(s): Tom Hallam, Professor Kevin MarchbankORCiD, Professor Claire Harris, Victoria Shuttleworth, Professor David KavanaghORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract Purpose: Rare genetic variants in complement factor I (CFI) that cause low systemic levels of the protein (FI) have been reported as a strong risk factor for advanced AMD. This study set out to replicate these findings. Methods: FI levels were measured by sandwich ELISA in an independent cohort of 276 AMD patients and 205 elderly controls. SNP genotyping and Sanger sequencing were used to assess genetic variability. Results: The median FI level was significantly lower (28.3μg/mL) in those individuals with AMD and a rare CFI variant compared to those with AMD without a rare CFI variant (38.8μg/mL P = 0.004) or the control population with (41.7μg/mL, P = 0.0085) or without (41.5μg/ml, P < 0.0001) a rare CFI variant. 35% of AMD patients with a rare CFI variant had levels below the 5th percentile, compared to 6% in controls with CFI variants. Multiple regression analyses revealed a decreased FI level associated with a rare CFI variant was a risk for AMD (Early or Late AMD: OR 12.04, P = 0.03; Early AMD: OR 30.3 P = 0.02; Late AMD: OR 10.64, P < 0.01). Additionally, measurement of FI in aqueous humour revealed a large FI concentration gradient between systemic circulation and the eye (~250 -fold). Conclusion: Rare genetic variants in CFI causing low systemic FI levels are strongly associated with AMD. The impermeability of the Bruch's membrane to FI will have implications for therapeutic replacement of FI in individuals with CFI variants and low FI levels at risk of AMD.

Publication metadata

Author(s): Hallam TM, Marchbank KJ, Harris CL, Osmond C, Shuttleworth VG, Griffiths H, Cree AJ, Kavanagh D, Lotery AJ

Publication type: Article

Publication status: Published

Journal: IOVS

Year: 2020

Volume: 61

Issue: 6

Print publication date: 09/06/2020

Online publication date: 09/06/2020

Acceptance date: 11/04/2020

Date deposited: 14/05/2020

ISSN (electronic): 1552-5783

Publisher: Association for Research in Vision and Ophthalmology


DOI: 10.1167/iovs.61.6.18


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Funder referenceFunder name
Alexion Pharmaceuticals
Complement UK
Fight for Sight
Gift of Sight appeal
Kidney Research UK
Medical Research Council
National Institute for Health Research (NIHR)
NIHR Senior Investigator award
the Wellcome Trust